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Stroke: Molecular mechanisms and therapies: Update on recent developments
Faheem Shehjar1, Briana Maktabi1, Zainab A Rahman1
1Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, Toledo, OH, USA.
Insights
This study explores novel stroke treatments, including the promising drug DM199 and cell-based therapies, aiming to improve outcomes for stroke survivors. Research focuses on understanding stroke mechanisms to develop effective therapeutic strategies.
Area of Science:
- Neurology
- Pharmacology
- Regenerative Medicine
Background:
- Stroke is a leading cause of death and disability globally, with significant economic impact.
- Complex pathophysiology involves atherosclerosis, thrombus, embolus, excitotoxicity, oxidative stress, and neuroinflammation.
- Current treatments like tPA have limitations, necessitating exploration of advanced therapeutic strategies.
Purpose of the Study:
- To review current and emerging therapeutic strategies for stroke.
- To highlight the potential of DM199 and cell-based therapies in stroke treatment.
- To understand the molecular mechanisms underlying stroke for targeted drug development.
Main Methods:
- Literature review of stroke pathophysiology and therapeutic interventions.
- Analysis of emerging treatments including DM199 and various stem cell therapies.
- Discussion of molecular mechanisms and risk factors associated with stroke.
Main Results:
- DM199, a synthetic KLK1, shows potential for stroke treatment with fewer side effects than tPA.
- Cell-based therapies (Neural Stem Cells, HSCs, HUCB-MSCs) are under investigation for stroke recovery.
- Existing therapies like GABA agonists and receptor inhibitors show promise but require combination strategies.
Conclusions:
- Developing effective stroke therapies requires understanding complex molecular mechanisms and risk factors.
- DM199 and cell-based therapies represent promising avenues for improving stroke patient outcomes.
- Continued research is crucial to minimize post-stroke damage and restore neurological function.
Abstract:
Stroke, a neurological disease, is one of the leading causes of death worldwide, resulting in long-term disability in most survivors. Annual stroke costs in the United States alone were estimated at $46 billion recently. Stroke pathophysiology is complex, involving multiple causal factors, among which atherosclerosis, thrombus, and embolus are prevalent. The molecular mechanisms involved in the pathophysiology are essential to understanding targeted drug development. Some common mechanisms are excitotoxicity and calcium overload, oxidative stress, and neuroinflammation. In addition, various modifiable and non-modifiable risk factors increase the chances of stroke manifolds. Once a patient encounters a stroke, complete restoration of motor ability and cognitive skills is often rare. Therefore, shaping therapeutic strategies is paramount for finding a viable therapeutic agent. Apart from tPA, an FDA-approved therapy that is applied in most stroke cases, many other therapeutic strategies have been met with limited success. Stroke therapies often involve a combination of multiple strategies to restore the patient's normal function. Certain drugs like Gamma-aminobutyric receptor agonists (GABA), Glutamate Receptor inhibitors, Sodium, and Calcium channel blockers, and fibrinogen-depleting agents have shown promise in stroke treatment. Recently, a drug, DM199, a recombinant (synthetic) form of a naturally occurring protein called human tissue kallikrein-1 (KLK1), has shown great potential in treating stroke with fewer side effects. Furthermore, DM199 has been found to overcome the limitations presented when using tPA and/or mechanical thrombectomy. Cell-based therapies like Neural Stem Cells, Hematopoietic stem cells (HSCs), and Human umbilical cord blood-derived mesenchymal stem cells (HUCB-MSCs) are also being explored as a treatment of choice for stroke. These therapeutic agents come with merits and demerits, but continuous research and efforts are being made to develop the best therapeutic strategies to minimize the damage post-stroke and restore complete neurological function in stroke patients.
